Safety, Tolerability and Pharmacokinetics (PK) Study of GSK2269557 in Healthy Subjects

A Randomised, Double-blind, Parallel Group Study to Evaluate the Safety, Tolerability and Pharmacokinetics of a Single Dose of GSK2269557 Administered Via the ELLIPTA™ Dry Powder Inhaler to Healthy Participants

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03189589

Enrollment

Registered

2017-06-16

Start date

2017-06-15

Completion date

2017-07-24

Last updated

2019-08-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Pulmonary Disease, Chronic Obstructive

Keywords

Pharmacokinetics, Healthy, ELLIPTA, Safety, GSK2269557, Inhalation, Tolerability

Brief summary

GSK2269557 is being developed as an anti-inflammatory and anti-infective agent for the treatment of inflammatory airways diseases. This is the first study using a new formulation of GSK2269557 in healthy subjects and will evaluate the safety, tolerability and PK of a single dose of GSK2269557. Data derived from this study will inform on the PK profile and systemic exposure expected during Phase 2b. Approximately twelve healthy subjects will be randomized to receive a single dose of GSK2269557 750 micrograms (µg) or a single dose of GSK2269557 500 µg via the ELLIPTA® dry powder inhaler (DPI) formulated in a blend containing 0.4 percent magnesium stearate (MgSt) in 1:1 ratio. This randomized, parallel group study will be carried out in 3 phases, including screening phase, treatment phase and follow-up phase. The total study duration for each subject will be up to 6 weeks. ELLIPTA is a registered trademark of GlaxoSmithKline group of companies.

Interventions

DRUGGSK2269557 500 µg

GSK2269557 is a potent and highly selective inhaled Phosphoinositide 3 Kinase delta inhibitor. Single dose of GSK2269557 500 µg will be administered to randomized subjects via inhalation route using ELLIPTA DPI.

DRUGGSK2269557 750 µg

GSK2269557 is a potent and highly selective inhaled Phosphoinositide 3 Kinase delta inhibitor. Single dose of GSK2269557 750 µg will be administered to randomized subjects via inhalation route using ELLIPTA DPI.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Masking description

This is a double-blind study and subjects and investigator will be blinded.

Intervention model description

Healthy subjects will be randomized to receive GSK2269557 750 µg or GSK2269557 500 µg.

Eligibility

Sex/Gender

ALL

Age

18 Years to 75 Years

Healthy volunteers

Yes

Inclusion criteria

* Subject must be 18 to 75 years of age inclusive, at the time of signing the informed consent. * Subjects who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and ECG tests. Re-screening will be allowed once, at the discretion of the Principal Investigator in consultation with GlaxoSmithKline (GSK) medical monitor. * Normal spirometry at Screening FEV1 and FVC \>=80 percent of predicted (measurements to be taken in triplicate and the highest value for each component must be \>=80 percent of predicted). * Body weight \>=50 kilograms (kg) and body mass index (BMI) within the range 18.0 - 35.0 kg per square meter (kg/m\^2) (inclusive). * Male or female: A male subject must agree to use contraception during the treatment period for at least 5 half-lives plus 90 days after the last dose of study treatment and refrain from donating sperm during this period. A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) or A WOCBP who agrees to follow the contraceptive guidance during the treatment period for at least 5 half-lives plus 90 days after the last dose of study treatment. * Capable of giving signed informed consent.

Exclusion criteria

* Asthma or a history of asthma (except in childhood, which has now remitted). * Significant history of or current cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study treatment; or interfering with the interpretation of data. * Abnormal blood pressure \[as determined by the investigator\]. * Alanine transaminase (ALT) \>1.5 times upper limit of normal (ULN). * Bilirubin \>1.5 times ULN (isolated bilirubin \>1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35 percent). * Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). * QTc interval \>450 milliseconds (msec). * Past or intended use of over-the-counter or prescription medication including herbal medications within 7 days prior to dosing. * Live vaccine(s) within 1 month prior to screening, or plans to receive such vaccines during the study. * Participation in the study would result in loss of blood or blood products in excess of 500 milliliters (mL) within 56 days. * Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day. Consider adding the following criteria if subjects can only be enrolled once per study. * Current enrollment or past participation within the last 90 days before signing of consent in any other clinical study involving an investigational study treatment or any other type of medical research * Presence of Hepatitis B surface antigen (HBsAg) at screening Positive Hepatitis C antibody test result at screening. Subjects with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C Ribonucleic Acid (RNA) test is obtained. * Positive Hepatitis C RNA test result at screening or within 3 months prior to first dose of study treatment. * Positive pre-study drug/alcohol screen. * Positive human immunodeficiency virus (HIV) antibody test. * Regular use of known drugs of abuse. * Regular alcohol consumption within 3 months prior to the study defined as: An average weekly intake of \>14 units for males and females. One unit is equivalent to 8 grams (g) of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits. * Current smoker or a history of smoking within 6 months of Screening, or a total pack year history of \>5 pack years. \[Number of pack years = (number of cigarettes per day/20) multiplied by number of years smoked\] * Sensitivity to any of the study treatments, or components thereof (including lactose and MgSt), or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study.

Design outcomes

Primary

Measure	Time frame	Description
Mean GSK2269557 Plasma Concentration	Day 1: Pre-dose, 5 minutes post dose, 30 minutes post-dose, 2 hours post-dose, 6 hours post-dose, 12 hours post-dose; Day 2: 24 hours post-dose; Day 3: 48 hours post-dose and Day 6: 120 hours post-dose	Whole blood samples of approximately 2 milliliters were collected for measurement of plasma concentrations of GSK2269557 at the indicated time points. The pharmacokinetic parameters were calculated by standard non-compartmental analysis. Pharmacokinetic (PK) Population which comprised of all randomized participants in the Safety Population and for whom a PK sample was obtained and analyzed.
Area Under the Plasma Drug Concentration Versus Time Curve (AUC) From Zero to Time t (AUC [0 to t]), AUC From Zero to 24 Hours (AUC [0 to 24]) and AUC From Zero to Infinity (AUC [0 to Inf]) of GSK2269557	Day 1: Pre-dose, 5 minutes post dose, 30 minutes post-dose, 2 hours post-dose, 6 hours post-dose, 12 hours post-dose; Day 2: 24 hours post-dose; Day 3: 48 hours post-dose and Day 6: 120 hours post-dose	Blood samples were collected to evaluate the PK of GSK2269557 at the indicated time points. The PK parameters were calculated by standard non-compartmental analysis. Only those participants with data available at the specified time points were analyzed represented by n=X in the category titles.
Maximum Observed Plasma Drug Concentration (Cmax) and Concentration at Trough (Ctrough) of GSK2269557	Day 1: Pre-dose, 5 minutes post dose, 30 minutes post-dose, 2 hours post-dose, 6 hours post-dose, 12 hours post-dose; Day 2: 24 hours post-dose; Day 3: 48 hours post-dose and Day 6: 120 hours post-dose	Blood samples were collected to evaluate the PK of GSK2269557 at the indicated time points. The PK parameters were calculated by standard non-compartmental analysis.
Time to Maximum Observed Plasma Drug Concentration (Tmax) and Terminal Half-life (t1/2)	Day 1: Pre-dose, 5 minutes post dose, 30 minutes post-dose, 2 hours post-dose, 6 hours post-dose, 12 hours post-dose; Day 2: 24 hours post-dose; Day 3: 48 hours post-dose and Day 6: 120 hours post-dose	Blood samples were collected to evaluate the PK of GSK2269557 at the indicated time points. The PK parameters were calculated by standard non-compartmental analysis. Only those participants with data available at the specified time points were analyzed represented by n=X in the category titles.

Secondary

Measure	Time frame	Description
Number of Participants With Clinical Chemistry Abnormalities of Potential Clinical Importance	Up to Day 2	Clinical chemistry parameters and their potential clinical concern range values were: calcium (low flag \<2 millimoles/Liter \[mmol/L\] and high flag \>2.75 mmol/L), creatinine (high flag \>44.2 micromoles/Liter increase in change from Baseline), glucose (fasting) (\<3 mmol/L and \>9 mmol/L), potassium (low flag \<3 mmol/L and high flag \>5.5 mmol/L above ULN), sodium (low flag \<130 mmol/L and high flag \>150 mmol/L). Number of participants with clinical chemistry abnormalities of potential clinical importance are presented.
Number of Participants With Vital Signs of Potential Clinical Importance	Up to Day 2	Vital signs included blood pressure (systolic and diastolic blood pressure) and heart rate measurements and were assessed with the participant in a semi-supine position after 5 minutes rest. The potential clinical concern range values for vital signs were: systolic blood pressure (lower \<85 millimeters of mercury and higher \>160 millimeters of mercury), diastolic blood pressure (lower \<45 millimeters of mercury and higher \>100 millimeters of mercury) and heart rate (lower \<40 beats per minute and higher \>110 beats per minute). Number of participants with vital signs of potential clinical importance are presented. Safety Population comprised of all randomized participants who received at least one dose of study treatment.
Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)	Up to 12 days post-dose	AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse. SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant.
Number of Participants With Electrocardiogram (ECG) Values of Potential Clinical Importance	Up to Day 2	Twelve-lead ECG was obtained using an ECG machine which automatically measured PR, QRS, QT and corrected QT (QTc) intervals. ECG parameters and their potential clinical importance range values were: absolute QTc interval (lower \>450 milliseconds \[msec\]), absolute PR interval (lower \<110 msec and upper \>220 msec), absolute QRS interval (lower \<75 msec and upper \>110 msec). Number of participants with electrocardiogram (ECG) values of potential clinical importance are presented.
Change From Baseline in Forced Vital Capacity (FVC) and Forced Expiratory Volume in 1 Second (FEV1)	Baseline and Day 1	The maximal amount of air forcefully exhaled in 1 second (FEV1) and forced vital capacity (FVC) was measured using a spirometer. Baseline was latest pre-dose assessment. Change from Baseline was calculated by subtracting Baseline values from post-dose visit values. Mean change from Baseline in FVC and FEV1 is presented.
Number of Participants With Hematology Abnormalities of Potential Clinical Importance	Up to Day 2	Hematology parameters and their potential clinical concern values were: Hematocrit (high flag: \>0.54 and change from Baseline: decrease of 0.075), hemoglobin (high flag: \>180 grams per Liter and change from Baseline: decrease of 25 grams per Liter), lymphocytes (low flag: \<0.8\10\^9 cells per Liter), neutrophil count (low flag: \<1.5\10\^9 cells per Liter), platelet count (low flag: \<100\10\^9 cells per Liter and high flag: \>550\10\^9 cells per Liter) and white blood cell count (low flag: \<3\10\^9 cells per Liter and high flag: \>20\10\^9 cells per Liter). Number of participants with hematology abnormalities of potential clinical importance are presented.

Countries

United Kingdom

Participant flow

Recruitment details

The study was conducted at a single center in the United Kingdom from 15-June-2017 to 24-July-2017.

Pre-assignment details

A total of 19 participants were screened for this study, of which 7 participants were screen failures and 12 participants were randomized to treatment. The reasons for screen failure were: did not meet inclusion/exclusion criteria (6 participants) and withdrawal by participant (1 participant).

Participants by arm

Arm	Count
GSK2269557 500 mcg Eligible participants received a single dose of GSK2269557 500 mcg via the ELLIPTA DPI on Day 1.	6
GSK2269557 750 mcg Eligible participants received a single dose of GSK2269557 750 mcg via the ELLIPTA DPI on Day 1.	6
Total	12

Baseline characteristics

Characteristic	GSK2269557 750 mcg	Total	GSK2269557 500 mcg
Age, Continuous	42.7 Years STANDARD_DEVIATION 10.98	48.3 Years STANDARD_DEVIATION 10.31	53.8 Years STANDARD_DEVIATION 6.21
Race/Ethnicity, Customized Black or African American	1 Participants	2 Participants	1 Participants
Race/Ethnicity, Customized White	5 Participants	10 Participants	5 Participants
Sex: Female, Male Female	0 Participants	0 Participants	0 Participants
Sex: Female, Male Male	6 Participants	12 Participants	6 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 6	0 / 6
other Total, other adverse events	3 / 6	3 / 6
serious Total, serious adverse events	0 / 6	0 / 6

Outcome results

Primary

Area Under the Plasma Drug Concentration Versus Time Curve (AUC) From Zero to Time t (AUC [0 to t]), AUC From Zero to 24 Hours (AUC [0 to 24]) and AUC From Zero to Infinity (AUC [0 to Inf]) of GSK2269557

Blood samples were collected to evaluate the PK of GSK2269557 at the indicated time points. The PK parameters were calculated by standard non-compartmental analysis. Only those participants with data available at the specified time points were analyzed represented by n=X in the category titles.

Time frame: Day 1: Pre-dose, 5 minutes post dose, 30 minutes post-dose, 2 hours post-dose, 6 hours post-dose, 12 hours post-dose; Day 2: 24 hours post-dose; Day 3: 48 hours post-dose and Day 6: 120 hours post-dose

Population: PK Population.

Arm	Measure	Group	Value (MEAN)	Dispersion
GSK2269557 500 mcg	Area Under the Plasma Drug Concentration Versus Time Curve (AUC) From Zero to Time t (AUC [0 to t]), AUC From Zero to 24 Hours (AUC [0 to 24]) and AUC From Zero to Infinity (AUC [0 to Inf]) of GSK2269557	AUC (0 to t), n=6,6	14032.8 Hours*picograms per milliliter	Standard Deviation 5027.09
GSK2269557 500 mcg	Area Under the Plasma Drug Concentration Versus Time Curve (AUC) From Zero to Time t (AUC [0 to t]), AUC From Zero to 24 Hours (AUC [0 to 24]) and AUC From Zero to Infinity (AUC [0 to Inf]) of GSK2269557	AUC (0 to 24), n=6,6	6000.6 Hours*picograms per milliliter	Standard Deviation 1646.07
GSK2269557 500 mcg	Area Under the Plasma Drug Concentration Versus Time Curve (AUC) From Zero to Time t (AUC [0 to t]), AUC From Zero to 24 Hours (AUC [0 to 24]) and AUC From Zero to Infinity (AUC [0 to Inf]) of GSK2269557	AUC (0 to inf), n=4,5	19291.7 Hours*picograms per milliliter	Standard Deviation 3788.1
GSK2269557 750 mcg	Area Under the Plasma Drug Concentration Versus Time Curve (AUC) From Zero to Time t (AUC [0 to t]), AUC From Zero to 24 Hours (AUC [0 to 24]) and AUC From Zero to Infinity (AUC [0 to Inf]) of GSK2269557	AUC (0 to t), n=6,6	18468.7 Hours*picograms per milliliter	Standard Deviation 7007.72
GSK2269557 750 mcg	Area Under the Plasma Drug Concentration Versus Time Curve (AUC) From Zero to Time t (AUC [0 to t]), AUC From Zero to 24 Hours (AUC [0 to 24]) and AUC From Zero to Infinity (AUC [0 to Inf]) of GSK2269557	AUC (0 to 24), n=6,6	8497.7 Hours*picograms per milliliter	Standard Deviation 3189.43
GSK2269557 750 mcg	Area Under the Plasma Drug Concentration Versus Time Curve (AUC) From Zero to Time t (AUC [0 to t]), AUC From Zero to 24 Hours (AUC [0 to 24]) and AUC From Zero to Infinity (AUC [0 to Inf]) of GSK2269557	AUC (0 to inf), n=4,5	23340.9 Hours*picograms per milliliter	Standard Deviation 6395.14

Primary

Maximum Observed Plasma Drug Concentration (Cmax) and Concentration at Trough (Ctrough) of GSK2269557

Blood samples were collected to evaluate the PK of GSK2269557 at the indicated time points. The PK parameters were calculated by standard non-compartmental analysis.

Population: PK Population.

Arm	Measure	Group	Value (MEAN)	Dispersion
GSK2269557 500 mcg	Maximum Observed Plasma Drug Concentration (Cmax) and Concentration at Trough (Ctrough) of GSK2269557	Cmax	2175.5 Picograms per milliliter	Standard Deviation 843.68
GSK2269557 500 mcg	Maximum Observed Plasma Drug Concentration (Cmax) and Concentration at Trough (Ctrough) of GSK2269557	Ctrough	171.8 Picograms per milliliter	Standard Deviation 48.71
GSK2269557 750 mcg	Maximum Observed Plasma Drug Concentration (Cmax) and Concentration at Trough (Ctrough) of GSK2269557	Cmax	1871.8 Picograms per milliliter	Standard Deviation 985.15
GSK2269557 750 mcg	Maximum Observed Plasma Drug Concentration (Cmax) and Concentration at Trough (Ctrough) of GSK2269557	Ctrough	248.9 Picograms per milliliter	Standard Deviation 71.92

Primary

Mean GSK2269557 Plasma Concentration

Whole blood samples of approximately 2 milliliters were collected for measurement of plasma concentrations of GSK2269557 at the indicated time points. The pharmacokinetic parameters were calculated by standard non-compartmental analysis. Pharmacokinetic (PK) Population which comprised of all randomized participants in the Safety Population and for whom a PK sample was obtained and analyzed.

Population: PK Population.

Arm	Measure	Group	Value (MEAN)	Dispersion
GSK2269557 500 mcg	Mean GSK2269557 Plasma Concentration	6 hours post-dose	259.7 Picograms per milliliter	Standard Deviation 81.6
GSK2269557 500 mcg	Mean GSK2269557 Plasma Concentration	12 hours post-dose	210.5 Picograms per milliliter	Standard Deviation 52.94
GSK2269557 500 mcg	Mean GSK2269557 Plasma Concentration	30 minutes post-dose	480.7 Picograms per milliliter	Standard Deviation 155.28
GSK2269557 500 mcg	Mean GSK2269557 Plasma Concentration	24 hours post-dose	171.8 Picograms per milliliter	Standard Deviation 48.71
GSK2269557 500 mcg	Mean GSK2269557 Plasma Concentration	5 minutes post-dose	2175.5 Picograms per milliliter	Standard Deviation 843.68
GSK2269557 500 mcg	Mean GSK2269557 Plasma Concentration	48 hours post-dose	114.0 Picograms per milliliter	Standard Deviation 38.31
GSK2269557 500 mcg	Mean GSK2269557 Plasma Concentration	2 hours post-dose	322.9 Picograms per milliliter	Standard Deviation 83.85
GSK2269557 500 mcg	Mean GSK2269557 Plasma Concentration	120 hours post-dose	36.3 Picograms per milliliter	Standard Deviation 19.3
GSK2269557 500 mcg	Mean GSK2269557 Plasma Concentration	Pre-dose	0.0 Picograms per milliliter	Standard Deviation 0
GSK2269557 750 mcg	Mean GSK2269557 Plasma Concentration	120 hours post-dose	40.1 Picograms per milliliter	Standard Deviation 26.37
GSK2269557 750 mcg	Mean GSK2269557 Plasma Concentration	Pre-dose	0.0 Picograms per milliliter	Standard Deviation 0
GSK2269557 750 mcg	Mean GSK2269557 Plasma Concentration	5 minutes post-dose	1871.8 Picograms per milliliter	Standard Deviation 985.15
GSK2269557 750 mcg	Mean GSK2269557 Plasma Concentration	30 minutes post-dose	530.7 Picograms per milliliter	Standard Deviation 260.82
GSK2269557 750 mcg	Mean GSK2269557 Plasma Concentration	2 hours post-dose	414.6 Picograms per milliliter	Standard Deviation 187.63
GSK2269557 750 mcg	Mean GSK2269557 Plasma Concentration	12 hours post-dose	319.5 Picograms per milliliter	Standard Deviation 109.94
GSK2269557 750 mcg	Mean GSK2269557 Plasma Concentration	24 hours post-dose	248.9 Picograms per milliliter	Standard Deviation 71.92
GSK2269557 750 mcg	Mean GSK2269557 Plasma Concentration	48 hours post-dose	145.2 Picograms per milliliter	Standard Deviation 40.54
GSK2269557 750 mcg	Mean GSK2269557 Plasma Concentration	6 hours post-dose	424.0 Picograms per milliliter	Standard Deviation 186.51

Primary

Time to Maximum Observed Plasma Drug Concentration (Tmax) and Terminal Half-life (t1/2)

Population: PK Population.

Arm	Measure	Group	Value (MEDIAN)
GSK2269557 500 mcg	Time to Maximum Observed Plasma Drug Concentration (Tmax) and Terminal Half-life (t1/2)	Tmax, n=6,6	0.083 Hours
GSK2269557 500 mcg	Time to Maximum Observed Plasma Drug Concentration (Tmax) and Terminal Half-life (t1/2)	t1/2, n=4,5	42.7 Hours
GSK2269557 750 mcg	Time to Maximum Observed Plasma Drug Concentration (Tmax) and Terminal Half-life (t1/2)	Tmax, n=6,6	0.083 Hours
GSK2269557 750 mcg	Time to Maximum Observed Plasma Drug Concentration (Tmax) and Terminal Half-life (t1/2)	t1/2, n=4,5	38.2 Hours

Secondary

Change From Baseline in Forced Vital Capacity (FVC) and Forced Expiratory Volume in 1 Second (FEV1)

The maximal amount of air forcefully exhaled in 1 second (FEV1) and forced vital capacity (FVC) was measured using a spirometer. Baseline was latest pre-dose assessment. Change from Baseline was calculated by subtracting Baseline values from post-dose visit values. Mean change from Baseline in FVC and FEV1 is presented.

Time frame: Baseline and Day 1